We conducted a general review of the literature to gain a better understanding of the regulatory mechanisms of alloimmunization in sickle-cell patients, and consequently improve risk control by implementing a preventive transfusion strategy wherever possible.Anti-erythrocyte alloimmunization represents a serious problem in polytransfused sickle-cell patients, especially in view of the increasing longevity of patients and the growing number of transfusion indications in the management of these patients. Although to date, the factors conditioning the occurrence of alloimmunization are largely unknown, published studies point to both genetic and non-genetic factors. Challenges remain in the diagnosis, prevention and management of alloimmunization in sickle cell disease. Understanding the mechanisms and associated risk factors will help to develop strategies to prevent and inhibit Ac production in transfused patients, and to preserve the potentially life-threatening prognosis.